The present invention provides a novel compound, novel compositions, methods of their use and methods of their manufacture, such compound pharmacologically useful in the treatment of hypertension, congestive heart failure and angina in mammals. More specifically, the compound of the present invention is an orally active renin-release inhibitor (as opposed to a direct-acting renin-inhibiting compound) agent which, by effectively blocking plasma renin activity, thereby blocks the production of angiotensin II, which is a powerful vasoconstrictor. Since renin is involved in the pathogenesis of hypertension, congestive heart failure and angina in mammals, it can be seen that the novel compound of the present invention is useful in the treatment of these pathological disease states.
Hypertension is a disease characterized by increased vascular resistance, increased arterial blood pressure, and, in some cases, increased plasma renin activity. Renin may be involved in the pathogenesis of hypertension even if its level is not elevated in the plasma.
The renin-angiotensin system exists in every vertebrate class studied. The main source of renin is the kidney, from which it is secreted by the granular juxtaglomerular cells that lie in the walls of the afferent arterioles as they enter the glomeruli. These are endocrine cells in the sense that they discharge their secretory product, renin, directly into the renal arterial blood stream. Their peculiarity lies in the fact that renin is not itself a hormone but is an enzyme that catalyzes the formation of the active hormones, the angiotensins. Renin and the other components of the renin-angiotensin system are also found at various extrarenal sites, including the brain. Renin, which is a protease with high substrate specificity, is both the initiating and the rate-limiting element in the production of the active peptide hormones. It releases the decapeptide angiotensin I by cleaving the peptide bond between residues #10 and #11 of its substrate, angiotensinogen. Angiotensinogens are glycoproteins, present in abundance in the plasma globulin fraction and synthesized by the liver. After renin acts on its substrate, angiotensinogen, to produce angiotensin I, angiotensin converting enzyme (ACE; Kininase II; Dipeptidyl Carboxypeptidase) catalyzes the conversion of angiotensin I into angiotensin II which is the classic vasoconstrictor agent with its powerful pressor effect.
U.S. Pat. No. 3,706,728 discloses that N(6)-alkyl-adenosine derivatives produce peripheral blood vessel dilating actions. It has been further taught that N(6)-[2-hydroxy-3-(1-naphthyloxy)propyl]-adenosine (I) binds to the adenosine Al receptor in the granular juxtaglomerular cells of the kidney to inhibit release of renin into the plasma, ultimately resulting in a reduction in circulating angiotensin II, thus reducing arterial blood pressure and heart rate in hypertensive models (Federation Proceedings 44:879 & 1643, 1985). Thus, this compound has an excellent profile for the treatment of hypertension and congestive heart failure and may also be useful in the treatment of angina.
One of the disadvantages of other adenosine analogs is that they produce sedation and generalized central nervous system depression. Thus, there is a need in this art for a renin inhibiting compound which has a decreased incidence of such side effects. It is an object of the present invention to produce a compound which will effectively inhibit the production of renin, and which will display a lowered incidence of the side effects of sedation and central nervous system depression.